RNA Binding Proteins as Drivers and Therapeutic Target Candidates in Pancreatic Ductal Adenocarcinoma.

Markus Glaß,Patrick Michl,Stefan Hüttelmaier

doi:10.3390/ijms21114190

Abstract

Pancreatic ductal adenocarcinomas (PDAC) belong to the most frequent and most deadly malignancies in the western world. Mutations in KRAS and TP53 along with some other frequent polymorphisms occur almost universally and are likely to be responsible for tumor initiation. However, these mutations cannot explain the heterogeneity in therapeutic responses observed in PDAC patients, which limits efficiency of current therapeutic strategies. Instead, recent classifications of PDAC tumor samples are based on transcriptomics data and thus include information about epigenetic, transcriptomic, and post-transcriptomic deregulations. RNA binding proteins (RBPs) are important post-transcriptional regulators involved in every aspect of the RNA life cycle and thus considerably influence the transcriptome. In this study, we systematically investigated deregulated expression, prognostic value, and essentiality reported for RBPs in PDAC or PDAC cancer models using publicly available data. We identified 44 RBPs with suggested oncogenic potential. These include various proteins, e.g., IGF2 mRNA binding proteins (IGF2BPs), with reported tumor-promoting roles. We further characterized these RBPs and found common patterns regarding their expression, interaction, and regulation by microRNAs. These analyses suggest four prime candidate oncogenic RBPs with partially validated target potential: APOBEC1, IGF2BP1 and 3, and OASL.

Highlights

Pancreatic cancer currently is the fourth leading cause of cancer-associated death in Western societies and predicted to become the second leading cause of death by 2030 [1,2]
In this study we identified 44 RNA binding proteins (RBPs) salient in the context of pancreatic ductal adenocarcinomas (PDAC) due to their elevated RNA expression and adverse prognostic values
We identified a network of coexpressed RBPs that are known to be part of the innate immune response against viral infections

Summary

Introduction

Pancreatic cancer currently is the fourth leading cause of cancer-associated death in Western societies and predicted to become the second leading cause of death by 2030 [1,2]. Bailey et al [1] derived four subclasses by applying NMF to RNA-seq and microarray data of pancreatic cancer samples: squamous, pancreatic progenitor, immunogenic, and aberrantly differentiated endocrine exocrine (ADEX) Application of these three classification systems to the RNA expression data provided by The Cancer Genome Atlas (TCGA) research network revealed that classification of the samples as basal-like or classical was independent of tumor purity. These subtypes were distinguished by differential regulation of gene expression by microRNAs (miRNAs) and DNA methylation [7]. Other RBPs with suggested tumor-promoting roles in PDAC include the 5’-3’ exonuclease EXO1 [21] and the RBPs HuR (ELAVL1) and PTBP3, which both have been reported to lead to hypoxia-induced chemoresistance in pancreatic cancer cells [22,23]

Methods

Results

Conclusion